Long non-coding RNA RAMS11 promotes metastatic colorectal cancer progression

Jessica M. Silva-Fisher, Ha X. Dang, Nicole M. White, Matthew S. Strand, Bradley A. Krasnick, Emily B. Rozycki, Gejae G. L. Jeffers, Julie G. Grossman, Maureen K. Highkin, Cynthia Tang, Christopher R. Cabanski, Abdallah Eteleeb, Jacqueline Mudd, S. Peter Goedegebuure, Jingqin Luo, Elaine R. Mardis, Richard K. Wilson, Timothy J. Ley, Albert C. Lockhart, Ryan C. Fields and Christopher A. Maher ()
Additional contact information
Jessica M. Silva-Fisher: Washington University School of Medicine
Ha X. Dang: Washington University School of Medicine
Nicole M. White: Washington University School of Medicine
Matthew S. Strand: Washington University School of Medicine
Bradley A. Krasnick: Washington University School of Medicine
Emily B. Rozycki: Washington University School of Medicine
Gejae G. L. Jeffers: Washington University School of Medicine
Julie G. Grossman: Washington University School of Medicine
Maureen K. Highkin: Washington University School of Medicine
Cynthia Tang: Washington University School of Medicine
Christopher R. Cabanski: Parker Institute for Cancer Immunotherapy
Abdallah Eteleeb: Washington University School of Medicine
Jacqueline Mudd: Washington University School of Medicine
S. Peter Goedegebuure: Washington University School of Medicine
Jingqin Luo: Washington University School of Medicine
Elaine R. Mardis: Nationwide Children’s Hospital
Richard K. Wilson: Nationwide Children’s Hospital
Timothy J. Ley: Washington University School of Medicine
Albert C. Lockhart: University of Miami
Ryan C. Fields: Washington University School of Medicine
Christopher A. Maher: Washington University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Colorectal cancer (CRC) is the most common gastrointestinal malignancy in the U.S.A. and approximately 50% of patients develop metastatic disease (mCRC). Despite our understanding of long non-coding RNAs (lncRNAs) in primary colon cancer, their role in mCRC and treatment resistance remains poorly characterized. Therefore, through transcriptome sequencing of normal, primary, and distant mCRC tissues we find 148 differentially expressed RNAs Associated with Metastasis (RAMS). We prioritize RAMS11 due to its association with poor disease-free survival and promotion of aggressive phenotypes in vitro and in vivo. A FDA-approved drug high-throughput viability assay shows that elevated RAMS11 expression increases resistance to topoisomerase inhibitors. Subsequent experiments demonstrate RAMS11-dependent recruitment of Chromobox protein 4 (CBX4) transcriptionally activates Topoisomerase II alpha (TOP2α). Overall, recent clinical trials using topoisomerase inhibitors coupled with our findings of RAMS11-dependent regulation of TOP2α supports the potential use of RAMS11 as a biomarker and therapeutic target for mCRC.

Date: 2020
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DOI: 10.1038/s41467-020-15547-8

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